Jessica A. San Juan, Khetpakorn Chakarawet, Zhecheng He, Rebeca L. Fernandez, Michael J. Stevenson, Nathaniel H. O. Harder, Samuel E. Janisse, Lee-Ping Wang, R. David Britt, Marie C. Heffern

Peptide hormones are essential signaling molecules with therapeutic importance. Identifying factors that drive their activity would lead to treatment of various diseases. C-peptide, a short-length protein derived from the same prohormone as insulin, exhibits beneficial effects particularly in diabetic patients, but its clinical use has been hampered by a lack of mechanistic understanding. In this work, we demonstrate the combined impact of copper(II) ion and serum albumin, the major protein component of blood, on the activity of C-peptide. We show that copper(II) ion mediates the formation of ternary complexes between albumin and C-peptide. These ternary complexes alter peptide’s redox protection and internalization of the peptide into cells. Altogether, we show the relevance of copper in mediating C-peptide transport and internalization, with potential application as a biomarker.

Keywords: C-peptide, copper, serum albumin, protein interactions, biomarkers

Reference: J. Am. Chem. Soc. 2023, 145, 16726 – 16738. DOI: 10.1021/jacs.3c04599